The laboratory is involved in studies of E-cadherin-dependent Langerhans cell-keratinocyte adhesion. We have determined that the homophilic adhesion molecule E-cadherin is expressed at high levels by murine and human epidermal Langerhans cells, but not by lymphoid dendritic cells. Some dendritic cells in skin-draining lymph nodes express low levels of E-cadherin; most likely these cells represent activated Langerhans cells that have recently entered the nodes. Studies of Langerhans cells during the initiation phase of contact sensitivity reactions indicate that one consequence of antigen-induced Langerhans cell activation is decreased expression of E-cadherin by Langerhans cells. We believe that decreased cadherin expression or function is a prerequisite for emigration of Langerhans cells from skin. IL-1beta and TNFalpha are known to be produced in epidermis within hours after contact allergen treatment; these cytokines also decrease Langerhans cell E-cadherin expression. To facilitate studies of Langerhans cell-keratinocyte interactions in vitro, we are defining culture conditions that permit propagation of Langerhans cells in vitro. Recently we determined that TGFbeta1 plays a role in Langerhans cell ontogeny, and we are using TGFbeta1 to facilitate growth of Langerhans cells in vitro. We previously observed that TGFbeta1 induced expression of the dendritic cell differentiation antigen gp40 by dendritic cells expanded from bone marrow, and that dendritic cells in TGFbeta1 null mice did not express gp40. Additional studies of TGF1 null mice revealed that although these animals have a normal contingent of lymphoid dendritic cells, they lacked epidermal Langerhans cells. TGFbeta1 null marrow gave rise to Langerhans cells in lethally-irradiated TGFbeta1-containing recipients, and normal Langerhans cells took up residence in skin grafts taken from TGFbeta1 null mice. Thus, the Langerhans cell defect in TGFbeta1 null mice does not result from an absolute deficiency in precursors or reflect an obvious inability of Langerhans cells to home to, or localize in, TGFbeta1 null skin. TGFbeta1 may serve as a growth factor (or cofactor) for Langerhans cells since TGFbeta1 markedly enhances the recovery of leukocytes that resemble Langerhans cells from GM-CSF-supplemented primary cultures of murine fetal skin cells. The potential utility of these cells in studies of Langerhans cell-keratinocyte interactions is being explored. Because it is already clear that fetal skin-derived Langerhans cells (which express high levels of E-cadherin) do not bind well to E-cadherin expressing substrates, we have begun a search for microenvironmental influences that may regulate E-cadherin affinity. We have determined that adult mouse epidermal cells and neonatal keratinocytes contain wnt-4 mRNA. Future experiments will determine the importance of epidermal wnt-4 gene expression in Langerhans cell-keratinocyte adhesion, Langerhans cell homing (and epidermal localization) and skin development.
